For the use of a Registered Medical Practitioner or a Hospital or a Institution only.

A POTENT ANTIDOTE TO FOLIC ACID ANTAGONIST

After High Dose Methotrexate Therapy

To Counteract the Effects of Impaired Methotrexate Elimination

Treatment of Megaloblastic Anaemias

In Combination with 5-Fluorouracil

DESCRIPTION:

Leucovorin Calcium is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs which act as folic acid antagonists. It is also known as folinic acid, Citrovorum factor, or 5-formyl-5,6,7,8-tetrahydrofolic acid. Chemically Leucovorin calcium is L-Glutamic acid, N-[4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amino] benzoyl]-, calcium salt (1:1). Its molecular formula is C20H21CaN7O7 and its molecular weight is 511.50.

ACTIONS :
Folinic acid (leucovorin) is the 5-formyl derivative of tetrahydrofolic acid (THF), the active form of folic acid. Folinic acid as a co-factor participates in many metabolic reactions including purine synthesis, pyrimidine synthesis and amino acid conversion. Calcium folinate is used in cytotoxic therapy as an antidote to folic acid antagonists (such as methotrexate) which block conversion of folic acid to tetrahydrofolate by binding the enzyme dihydrofolate reductase.

PHARMACOKINETICS :
Following administration, calcium folinate enters the general body pool of reduced folates. It has been reported that following intravenous and intramuscular administration peak serum levels of total reduced folates are achieved within a mean time of 10 minutes and 52 minutes respectively. Peak levels of 5-formyl THF appear at 10 minutes and 28 minutes following intravenous and intramuscular administration respectively. Reduction in the levels of parent compound coincides with the appearance of the active metabolite 5-methyl THF which becomes the major circulating form of the drug. Peak levels are observed at 1.5 and 2.8 hours following intravenous and intramuscular administration respectively. The terminal half life for total reduced folates is reported as 6.2 hours. Folate is concentrated in the cerebrospinal fluid although distribution occurs to all body tissues. Folates are excreted in the urine.

INDICATIONS :
Leucovorin calcium rescue is indicated after high dose methotrexate therapy in osteosarcoma. Leucovorin calcium is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists. Leucovorin calcium is indicated in the treatment of megaloblastic anaemias due to folic acid deficiency when oral therapy is not feasible. Leucovorin is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Leucovorin should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.

DOSAGE AND ADMINISTRATION:

Administration :
Leucovorin Calcium Injection USP may be administered by the intramuscular or intravenous route. Calcium folinate should not be administered intrathecally. When required for intravenous infusion, Leucovorin Calcium Injection USP may be diluted in glucose 5 % or sodium chloride 0.9 %, both in water for injections. Further diluted solutions of calcium folinate in glucose 5 % intravenous infusion and sodium chloride 0.9 % intravenous infusion are stable for 24 hours when stored between 2-8°C. Admixed solutions for parenteral administration should be visually inspected for particulate matter and discolouration prior to administration where solution and container permit. Do not use if solution is cloudy or precipitated.

Incompatabilities :
Leucovorin Calcium Injection USP has been reported to be incompatible with droperidol injection and foscarnet injection. Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.

Dosage :Advanced Colorectal Cancer :
Either of the following two regimens is recommended :

1.Leucovorin is administered at 200 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m2 by intravenous injection.
2.Leucovorin is administered at 20 mg/m2 by intravenous injection followed by 5-fluorouracil at 425 mg/m2 by intravenous injection.

5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate. Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course. In subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-fluorouracil should be reduced by 20 % for patients who experienced moderate haematologic or gastrointestinal toxicity in the prior treatment course, and by 30 % for patients who experienced severe toxicity. For patients who experienced no toxicity in the prior treatment course, 5-fluorouracil dosage may be increased by 10 %. Leucovorin dosages are not adjusted for toxicity.

Leucovorin Rescue After High-Dose Methotrexate Therapy:
The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m2 administered by intravenous infusion over 4 hours. Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally.

Do not administer leucovorin intrathecally.
Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

Impaired Methotrexate Elimination or Inadvertent Overdosage :
Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is a delayed excretion. Leucovorin 10 mg/m2 should be administered I.M., I.V., or PO every 6 hours until the serum methotrexate level is less than 10-8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally. Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50 % over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of leucovorin should be increased to 100 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M. Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

Megaloblastic Anaemia Due to Folic Acid Deficiency :
Up to 1 mg daily. There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg. Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 ml of a 10 mg/ml, or 8 ml of a 20 mg/ml solution per minute).

CONTRAINDICATIONS :
Folinic acid should not be used for the treatment of pernicious anaemia or other megaloblastic anaemias secondary to vitamin B12 deficiency.

WARNINGS :
In the treatment of accidental overdosages of folic acid antagonists, intravenous leucovorin should be administered as promptly as possible. As the time interval between antifolate administration (e.g., methotrexate) and leucovorin rescue increases, leucovorins effectiveness in counteracting toxicity decreases. In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not administer leucovorin intrathecally. LEUCOVORIN MAY BE HARMFUL OR FATAL IF GIVEN INTRATHECALLY.
Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. Delayed methotrexate excretion may be caused by a third space fluid accumulation (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of leucovorin or prolonged administration may be indicated. Doses higher than those recommended for oral use must be given intravenously. Leucovorin enhances the toxicity of 5-fluorouracil. When these drugs are administered concurrently in the palliative therapy of advanced colorectal cancer, the dosage of 5-fluorouracil must be lower than usually administered. Although the toxicities observed in patients treated with the combination of leucovorin plus 5-fluorouracil are qualitatively similar to those observed in patients treated with 5-fluorouracil alone, gastrointestinal toxicities (particularly stomatitis and diarrhoea) are observed more commonly and may be more severe and of prolonged duration in patients treated with the combination.

Seizures and/or syncope have been reported rarely in cancer patients receiving leucovorin, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors, however, a causal relationship has not been established. The concomitant use of leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study.

PRECAUTIONS :General :
Parenteral administration is preferable to oral dosing if there is a possibility that the patient may vomit and not absorb the leucovorin. Leucovorin has no effect on non-haematologic toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney. Since leucovorin enhances the toxicity of fluorouracil, leucovorin/5-fluorouracil combination therapy for advanced colorectal cancer should be administered under the supervision of a physician experienced in the use of antimetabolite cancer chemotherapy. Particular care should be taken in the treatment of elderly or debilitated colorectal cancer patients, as these patients may be at increased risk of severe toxicity.

PREGNANCY AND LACTATION:

Pregnancy : Pregnancy Category C
Adequate animal reproduction studies have not been conducted with leucovorin. It is also not known whether leucovorin can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. Leucovorin should be given to a pregnant woman only if clearly needed.

Lactation :
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when leucovorin is administered to a nursing mother.

Laboratory Tests :
Patients being treated with the leucovorin/5-fluorouracil combination should have a CBC with differential and platelets prior to each treatment. During the first two courses a CBC with differential and platelets has to be repeated weekly and thereafter once each cycle at the time of anticipated WBC nadir. Electrolytes and liver function tests should be performed prior to each treatment for the first three cycles then prior to every other cycle. Dosage modifications of fluorouracil should be instituted as follows, based on the most severe toxicities.

If no toxicity occurs, the 5-fluorouracil dose may increase 10 %. Treatment should be deferred until WBCs are 4,000/mm3 and platelets 130,000/mm3. If blood counts do not reach these levels within two weeks, treatment should be discontinued. Patients should be followed up with physical examination prior to each treatment course and appropriate radiological examination as needed. Treatment should be discontinued when there is clear evidence of tumor progression.

INTERACTIONS :
Calcium folinate may enhance the toxicity of fluoropyrimidines e.g. 5-fluorouracil. Deaths from severe enterocolitis, diarrhoea and dehydration have been reported in elderly patients receiving fluorouracil and calcium folinate. Concomitant granulocytopaenia and fever were present in some but not all patients. Folic acid in large amounts may counteract the antiepileptic effect of phenobarbitone, phenytoin and primidone, and increase the frequency of seizures in susceptible children.

SIDE EFFECTS :
Adverse reactions to calcium folinate are rare. Occasional hypersensitivity reactions have been reported; pyrexia and urticaria have occurred after parenteral administration. Nausea and vomiting with very high doses of calcium folinate have been reported. Seizures and/or syncope have been reported rarely in cancer patients receiving calcium folinate, usually in association with fluoropyrimidine administration.

OVERDOSAGE :
Folinic acid is an intermediate in the metabolism of folic acid and can therefore be considered as a naturally occurring substance. Large doses have been administered with no apparent adverse effects. Such doses suggest that administration of this drug is relatively safe.

TREATMENT OF OVERDOSAGE :
Signs of excessive dosing, if they occur, should be treated symptomatically. Excessive amounts of calcium folinate may nullify the chemotherapeutic effect of folic acid antagonists.

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